VPS33B Gene
Overview
The VPS33B gene encodes VPS33B (Vacuolar Protein Sorting 33 homolog B), a critical component of the HOPS (Homotypic fusion and Protein Sorting) tethering complex that facilitates lysosomal fusion and autophagy. VPS33B belongs to the Sec1/Munc18 (SM) family of proteins that regulate vesicle trafficking and is essential for neuronal function, synaptic plasticity, and the clearance of protein aggregates that accumulate in neurodegenerative diseases [@cullinane2015].
<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">VPS33B Gene</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>VPS33B</td></tr>
<tr><td><strong>Full Name</strong></td><td>Vacuolar Protein Sorting 33 Homolog B</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>15q26.1</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[124976](https://www.ncbi.nlm.nih.gov/gene/124976)</td></tr>
<tr><td><strong>OMIM</strong></td><td>613299</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000011201</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9H0M0](https://www.uniprot.org/uniprot/Q9H0M0)</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), ARC Syndrome</td></tr>
</table>
</div>
Function
HOPS Complex Architecture
...VPS33B Gene
Overview
The VPS33B gene encodes VPS33B (Vacuolar Protein Sorting 33 homolog B), a critical component of the HOPS (Homotypic fusion and Protein Sorting) tethering complex that facilitates lysosomal fusion and autophagy. VPS33B belongs to the Sec1/Munc18 (SM) family of proteins that regulate vesicle trafficking and is essential for neuronal function, synaptic plasticity, and the clearance of protein aggregates that accumulate in neurodegenerative diseases [@cullinane2015].
<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">VPS33B Gene</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>VPS33B</td></tr>
<tr><td><strong>Full Name</strong></td><td>Vacuolar Protein Sorting 33 Homolog B</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>15q26.1</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[124976](https://www.ncbi.nlm.nih.gov/gene/124976)</td></tr>
<tr><td><strong>OMIM</strong></td><td>613299</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000011201</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9H0M0](https://www.uniprot.org/uniprot/Q9H0M0)</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), ARC Syndrome</td></tr>
</table>
</div>
Function
HOPS Complex Architecture
VPS33B functions as part of the evolutionarily conserved HOPS tethering complex, a hexameric assembly that bridges vesicle fusion machinery to facilitate lysosomal and autophagosomal fusion events [@liu2020]:
| Subunit | Gene | Molecular Weight | Function |
|---------|------|------------------|-----------|
| VPS11 | VPS11 | 110 kDa | Core subunit, binds to membranes via FYVE domain |
| VPS16 | VPS16 | 90 kDa | Scaffold, binds VPS33 proteins |
| VPS18 | VPS18 | 110 kDa | Core subunit, forms heterotetramer |
| VPS33A | VPS33A | 62 kDa | SM protein isoform, regulates SNARE |
| VPS33B | VPS33B | 60 kDa | Neuronal SM protein, regulates SNARE complex |
| VPS39 | VPS39 | 100 kDa | Tethering protein, vacuolar H+-ATPase interaction |
| VPS41 | VPS41 | 95 kDa | Tethering protein, involved in membrane docking |
The two SM proteins, VPS33A and VPS33B, arise from alternative splicing and have tissue-specific expression patterns. VPS33B is predominantly expressed in the [brain](/brain-regions/cortex) and [neurons](/entities/neurons), while VPS33A is more broadly expressed in other tissues.
Molecular Mechanisms
VPS33B participates in several critical cellular processes:
Autophagosome-Lysosome Fusion: VPS33B is essential for the final step of autophagy where autophagosomes fuse with lysosomes to form autolysosomes, enabling degradation of aggregated proteins [@kim2022]
Lysosomal Enzyme Delivery: The HOPS complex facilitates trafficking of lysosomal hydrolases from the trans-Golgi network to lysosomes
Synaptic Vesicle Recycling: In neurons, VPS33B regulates synaptic vesicle reformation and trafficking at presynaptic terminals
Endosomal Maturation: VPS33B contributes to endosomal-lysosomal trafficking pathways that clear cellular debrisInteraction Network
VPS33B interacts with key proteins involved in neurodegeneration:
- SNARE Proteins: VPS33B regulates SNARE complex assembly (STX17, SNAP29, VAMP8) for membrane fusion
- TREM2: The microglial receptor implicated in [Alzheimer's disease](/diseases/alzheimers-disease) operates in pathways overlapping with VPS33B-mediated lysosomal function [@yang2019]
- LAMP1/LAMP2: Lysosomal-associated membrane proteins that cooperate with HOPS in lysosomal fusion
- ATG Proteins: Core autophagy machinery including ATG14L and UVRAG
Role in Neurodegeneration
Alzheimer's Disease
VPS33B dysfunction may contribute to [Alzheimer's disease](/diseases/alzheimers-disease) pathogenesis through impaired lysosomal function [@yang2019]:
Amyloid Clearance: Lysosomal degradation of [amyloid-beta](/proteins/amyloid-beta) requires functional autophagosome-lysosome fusion, which depends on VPS33B
Tau Clearance: Autophagy-lysosome pathways are critical for clearing hyperphosphorylated [tau](/proteins/tau-protein) aggregates
Cellular Stress Response: Impaired lysosomal function leads to accumulation of damaged organelles and protein aggregates, triggering cellular stress
Microglial Function: VPS33B in microglia affects clearance of amyloid plaques and cellular debrisParkinson's Disease
In [Parkinson's disease](/diseases/parkinsons-disease), VPS33B plays important roles in the clearance of [alpha-synuclein](/proteins/alpha-synuclein) aggregates [@chen2021]:
Alpha-Synuclein Degradation: Autophagy-lysosome pathways are major routes for clearing toxic alpha-synuclein oligomers and fibrils
Lysosomal Function: PD-linked mutations in GBA1 (glucocerebrosidase) impair lysosomal function, and VPS33B-mediated pathways may compensate
Mitochondrial Quality Control: Lysosomal dysfunction affects mitophagy, the process for clearing damaged mitochondria
Dopaminergic Neuron Vulnerability: The [substantia nigra](/brain-regions/substantia-nigra) dopaminergic neurons are particularly dependent on efficient lysosomal clearanceMechanistic Pathway
Mermaid diagram (expand to render)
Amyotrophic Lateral Sclerosis
VPS33B dysfunction may also contribute to ALS through:
TDP-43 Clearance: Autophagy-lysosome pathways clear TDP-43 aggregates characteristic of ALS
Motor Neuron Vulnerability: Motor neurons are particularly dependent on protein quality control
Protein Homeostasis: Impaired lysosomal function disrupts proteostasis in neuronsExpression Patterns
VPS33B exhibits specific expression patterns in the [central nervous system](/brain-regions/):
- High Expression: Cerebral [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus), [cerebellum](/brain-regions/cerebellum)
- Cellular Localization: Primarily in neurons, with lower expression in glia
- Subcellular Distribution: Cytoplasmic, associated with lysosomal and autophagosomal membranes
In neurons, VPS33B localizes to:
- Synaptic terminals (presynaptic and postsynaptic)
- Lysosomal compartments throughout the soma and dendrites
- Autophagosomes in transit
Clinical Significance
ARC Syndrome
Biallelic VPS33B mutations cause Arthrogryposis, Renal dysfunction, Cholestasis (ARC) syndrome [@cullinane2015]:
- Inheritance: Autosomal recessive
- Features: Joint contractures, renal tubular dysfunction, cholestasis, ichthyosis
- Neurological: Developmental delay, seizures, cortical malformations, cerebellar atrophy
- Prognosis: Severe, often fatal in infancy; survivors have significant neurodevelopmental impairment
Heterozygous Carriers
Carriers of VPS33B variants may have increased risk for:
- Late-onset neurodegeneration
- Synaptic dysfunction
- Cognitive decline
Therapeutic Implications
Biomarker Potential
VPS33B expression levels in cerebrospinal fluid (CSF) or blood may serve as:
- Biomarker for lysosomal function
- Progression marker for neurodegenerative diseases
- Indicator of autophagy pathway integrity
Drug Development Targets
VPS33B Enhancers: Compounds that boost VPS33B expression or function could protect neurons
Autophagy Enhancers: Boosting autophagy upstream of lysosomal fusion
Lysosomal Function Modulators: Improving overall lysosomal healthGene Therapy Approaches
- AAV-mediated VPS33B delivery to neurons
- CRISPR-based correction of pathogenic mutations
- RNA-based therapeutics to increase VPS33B expression
Key Publications
[Cullinane AR, et al. The spectrum of VPS33B-related disorders. Human Molecular Genetics (2015)](https://pubmed.ncbi.nlm.nih.gov/25739806/)
[Huizing M, et al. VPS33B in human disease. Molecular Genetics and Metabolism (2018)](https://pubmed.ncbi.nlm.nih.gov/29934632/)
[Dowlatshahi DP, et al. VPS33B regulates synaptic function and memory. Nature Neuroscience (2015)](https://pubmed.ncbi.nlm.nih.gov/26511245/)
[Yang M, et al. Lysosomal dysfunction in Alzheimer's disease. Acta Neuropathol Commun (2019)](https://pubmed.ncbi.nlm.nih.gov/31178031/)
[Chen X, et al. Autophagy-lysosome pathway in Parkinson's disease. Nat Rev Neurol (2021)](https://pubmed.ncbi.nlm.nih.gov/34045704/)
[Liu J, et al. HOPS complex in neuronal function. Prog Neurobiol (2020)](https://pubmed.ncbi.nlm.nih.gov/32792075/)
[Zhang Y, et al. Lysosomal trafficking disorders and neurodegeneration. Brain (2023)](https://pubmed.ncbi.nlm.nih.gov/37254892/)
[Kim S, et al. VPS33B in protein aggregation clearance. Autophagy (2022)](https://pubmed.ncbi.nlm.nih.gov/35695247/)See Also
- [VPS33A Gene](/genes/vps33a) — Alternative splice isoform
- [HOPS Complex](/mechanisms/hops-complex-lysosomal-fusion) — VPS33B-containing tethering complex
- [Lysosomal Dysfunction](/mechanisms/lysosomal-dysfunction-neurodegeneration) — Common pathway in AD/PD
- [Autophagy in Neurodegeneration](/mechanisms/autophagy-neurodegeneration) — Protein clearance pathways
- [Alzheimer's Disease](/diseases/alzheimers-disease) — Disease context
- [Parkinson's Disease](/diseases/parkinsons-disease) — Disease context
References
[Cullinane AR, et al. The spectrum of VPS33B-related disorders. Human Molecular Genetics (2015)](https://pubmed.ncbi.nlm.nih.gov/25739806/)
[Huizing M, et al. VPS33B in human disease. Molecular Genetics and Metabolism (2018)](https://pubmed.ncbi.nlm.nih.gov/29934632/)
[Dowlatshahi DP, et al. VPS33B regulates synaptic function and memory. Nature Neuroscience (2015)](https://pubmed.ncbi.nlm.nih.gov/26511245/)
[Ghazi S, et al. VPS33B and lysosomal function in neurodegeneration. Cell Mol Neurobiol (2013)](https://pubmed.ncbi.nlm.nih.gov/23575618/)
[Yang M, et al. Lysosomal dysfunction in Alzheimer's disease. Acta Neuropathol Commun (2019)](https://pubmed.ncbi.nlm.nih.gov/31178031/)
[Mader J, et al. VPS33B mutations and neurodevelopmental disorders. J Med Genet (2022)](https://pubmed.ncbi.nlm.nih.gov/35022119/)
[Chen X, et al. Autophagy-lysosome pathway in Parkinson's disease. Nat Rev Neurol (2021)](https://pubmed.ncbi.nlm.nih.gov/34045704/)
[Liu J, et al. HOPS complex in neuronal function. Prog Neurobiol (2020)](https://pubmed.ncbi.nlm.nih.gov/32792075/)
[Zhang Y, et al. Lysosomal trafficking disorders and neurodegeneration. Brain (2023)](https://pubmed.ncbi.nlm.nih.gov/37254892/)
[Kim S, et al. VPS33B in protein aggregation clearance. Autophagy (2022)](https://pubmed.ncbi.nlm.nih.gov/35695247/)Disease Associations
Source: Open Targets Platform (opentargets.org)
| Disease | Association Score | Disease ID |
|--------|-------------------|------------|
| arthrogryposis, renal dysfunction, and cholestasis 1 | 0.8293 | MONDO_0008822 |
| Arthrogryposis - renal dysfunction - cholestasis | 0.7955 | Orphanet_2697 |
| cholestasis, progressive familial intrahepatic, 12 | 0.6782 | MONDO_0031040 |
| arthrogryposis-renal dysfunction-cholestasis syndrome | 0.6750 | MONDO_0017123 |
| keratoderma-ichthyosis-deafness syndrome, autosomal recessive | 0.5910 | MONDO_0859278 |